62 research outputs found
Changes in MicroRNA Expression during Rabbit Hemorrhagic Disease Virus (RHDV) Infection.
Current knowledge on the role of microRNAs (miRNAs) in rabbit hemorrhagic disease
virus (RHDV) infection and the pathogenesis of rabbit hemorrhagic disease (RHD) is still limited.
RHDV replicates in the liver, causing hepatic necrosis and liver failure. MiRNAs are a class of short
RNA molecules, and their expression profiles vary over the course of diseases, both in the tissue
environment and in the bloodstream. This paper evaluates the expression of miRNAs in the liver
tissue (ocu-miR-122-5p, ocu-miR-155-5p, and ocu-miR-16b-5p) and serum (ocu-miR-122-5p) of rabbits
experimentally infected with RHDV. The expression levels of ocu-miR-122-5p, ocu-miR-155-5p,
and ocu-miR-16b-5p in liver tissue were determined using reverse transcription quantitative real-time
PCR (RT-qPCR), and the expression level of circulating ocu-miR-122-5p was established using
droplet digital PCR (ddPCR). The expression levels of ocu-miR-155-5p and ocu-miR-16b-5p were
significantly higher in the infected rabbits compared to the healthy rabbits (a fold-change of 5.8 and 2.5,
respectively). The expression of ocu-miR-122-5p was not significantly di�erent in the liver tissue from
the infected rabbits compared to the healthy rabbits (p = 0.990), while the absolute expression level of
the circulating ocu-miR-122-5p was significantly higher in the infected rabbits than in the healthy
rabbits (p < 0.0001). Furthermore, a functional analysis showed that ocu-miR-155-5p, ocu-miR-16b-5p,
and ocu-miR-122-5p can regulate the expression of genes involved in processes correlated with acute
liver failure (ALF) in rabbits. Search tool for the retrieval of interacting genes/proteins (STRING)
analysis showed that the potential target genes of the three selected miRNAs may interact with
each other in di�erent pathways. The results indicate the roles of these miRNAs in RHDV infection
and over the course of RHD and may reflect hepatic inflammation and impairment/dysfunction
in RHD
Study of a mechanism responsible for potential antidepressant activity of EMD 386088, a 5-HT_6 partial agonist in rats
It was shown that 5-HT(6) receptor agonists can exert pharmacological activity due to various modifications in monoamines’ level and metabolism activity in rats’ brain structures. This finding was correlated with antidepressant- or anxiolytic-like properties of these compounds. The study was designed to establish a possible mechanism of the antidepressant-like activity of the partial 5-HT(6) receptor agonist EMD386088 (5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole hydrochloride) in rats. The concentrations of monoamines (dopamine (DA), noradrenaline (NA), and serotonin (5-HT)) and the rate of their metabolism were measured ex vivo in the brain structures (hippocampus, nucleus accumbens, striatum) using high-performance liquid chromatography (HPLC). The rats were killed after the forced swim test (FST); the collected tissue samples were used to ex vivo experiments. The potency of EMD386088 to blockade dopamine transporter (DAT) was tested in a functional in vitro study. FST was used to assess the involvement of D(1)- and D(2)-like receptor subfamilies in antidepressant-like properties of EMD386088. Neurochemical data from ex vivo experiments showed that antiimmobility activity of EMD386088 may be connected with the activation of dopaminergic system, while neither noradrenergic nor serotonergic ones are involved in its effect. EMD386088 also possesses a significant affinity for DAT which may be a mechanism in the abovementioned effect. Behavioral data seem to confirm the importance of dopaminergic system activation in antidepressant-like activity of EMD386088, since this effect, observed in the FST, was abolished by the preferential D(1)- and D(2)-like receptor subfamily antagonists SCH23390 and sulpiride, respectively. Dopaminergic system is involved in antidepressant-like activity of EMD386088
Changes in the brain endocannabinoid system in rat models of depression
A growing body of evidence implicates the endocannabinoid (eCB) system in the pathophysiology of depression. The aim of this study was to investigate the influence of changes in the eCB system, such as levels of neuromodulators, eCB synthesizing and degrading enzymes, and cannabinoid (CB) receptors, in different brain structures in animal models of depression using behavioral and biochemical analyses. Both models used, i.e., bulbectomized (OBX) and Wistar Kyoto (WKY) rats, were characterized at the behavioral level by increased immobility time. In the OBX rats, anandamide (AEA) levels were decreased in the prefrontal cortex, hippocampus, and striatum and increased in the nucleus accumbens, while 2-arachidonoylglycerol (2-AG) levels were increased in the prefrontal cortex and decreased in the nucleus accumbens with parallel changes in the expression of eCB metabolizing enzymes in several structures. It was also observed that CB(1) receptor expression decreased in the hippocampus, dorsal striatum, and nucleus accumbens, and CB(2) receptor expression decreased in the prefrontal cortex and hippocampus. In WKY rats, the levels of eCBs were reduced in the prefrontal cortex (2-AG) and dorsal striatum (AEA) and increased in the prefrontal cortex (AEA) with different changes in the expression of eCB metabolizing enzymes, while the CB(1) receptor density was increased in several brain regions. These findings suggest that dysregulation in the eCB system is implicated in the pathogenesis of depression, although neurochemical changes were linked to the particular brain structure and the factor inducing depression (surgical removal of the olfactory bulbs vs. genetic modulation)
Study on the effect of EMD386088, a 5-HT_6 receptor partial agonist, in enhancing the anti-immobility action of some antidepressants in rats
The subtype selectivity in search of potent hypotensive agents among 5,5-dimethylhydantoin derived -adrenoceptors antagonists
Are the hydantoin-1,3,5-triazine ligands a hope to a find new procognitive and anti-obesity drug? : considerations based on primary in vivo assays and ADME-Tox profile in vitro
Though the serotonin receptor is an important target giving both agonists and
antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no ligand
has reached the pharmaceutical market yet due to the too narrow chemical space of the known
agents and insuffcient "drugability." Recently, a new group of non-indole and non-sulfone
hydantoin-triazine ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-
1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the
most active member. This study is focused on wider pharmacological and "druglikeness"
characteristics for KMP-10. A computer-aided insight into molecular interactions with
has been performed. "Druglikeness" was examined using an eight-test panel in vitro, i.e., a parallel
artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp)
affnity-, plasma protein binding-, metabolic stability- and drug–drug interaction-assays, as well
as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated
plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on
the influence of KMP-10 on rats' metabolism, including biochemical tests, were conducted in vivo.
Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity
properties in vivo, and it was found to satisfy the "druglikeness" profile in vitro for KMP-10. The
compound seems to be a good lead-structure and candidate for wider pharmacological studies in
search for new CNS-drugs acting via
Antidepressant- and anxiolytic-like effects of new dual 5-HT_{1A} and 5-HT_{7} antagonists in animal models
The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14-FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15-FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds
Discovery of novel pERK1/2- or -arrestin-preferring 5-HT receptor-biased agonists : diversified therapeutic-like versus side effect profile
Chlorine substituents and linker topology as factors of activity for novel highly active 1,3,5-triazine derivatives with procognitive properties in vivo
Hydrophobicity modulation via the substituents at positions 2 and 4 of 1,3,5-triazine to enhance therapeutic ability against Alzheimer's disease for potent serotonin 5-HT6R agents
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